Lignans are phytoestrogens which have been studied fairly extensively as dietary factors in breast cancer etiology due to structural and functional similarities to endogenous estrogens. Individual variation in metabolism is critical to consider when interpreting associations between dietary exposures and subsequent disease risk, and may partly explain inconsistencies in studies of diet and breast cancer. In fact, accumulating evidence supports the hypothesis that the effect of a dietary component, e.g. lignans, may be expressed differentially for individuals possessing specific variation in genes involved either in the metabolism of the dietary component and/or that of the non-dietary metabolic target. Also, to become physiologically active, plant lignans require transformation by the mammalian gut bacteria. These bacteria are numerous, diverse, and essential to the metabolism of dietary components; thus, gut bacterial composition is becoming a target for examination as an important contributor to and modifier of dietary exposures. Finally, race may also be an important effect modifier, as the concept of race incorporates genetic diversity, microbial diversity, and lifestyle factors including diet. The objective in the present study is to determine how variation in gut microbial community composition and in steroid hormone and xenobiotic metabolizing genes affects the metabolism of mammalian lignans and steroid hormones at baseline and after exposure to a lignan-rich food (flaxseed), and how these associations differ for African American and Caucasian women. Humans are, in fact, superorganisms with a diverse genetic background that is augmented by diverse and metabolically active bacterial communities, the composition of which can be modified by specific dietary exposures. Our central hypothesis is that the metabolic response to a dietary component results from the combined effects of an individual's genetic makeup and the particular composition of that individual's gut bacterial communities. Elucidation of interactions between the gut microbiome, host genetics, and diet will have a positive impact on development of improved targeted dietary interventions to reduce cancer risk. PUBLIC HEALTH RELEVANCE: Previous studies of diet and cancer have often produced inconsistent results, possibly because an individual's response to dietary exposures might be determined by their individual differences in metabolism. We propose to examine the effect of individual differences in gut bacterial community composition, genes, and race on hormone metabolism after a flaxseed intervention in healthy postmenopausal women.